[Rich66]

Clin Cancer Res. 2009 Jan 1;15(1):190-200.
RRR-alpha-vitamin E succinate potentiates the antitumor effect of calcitriol in prostate cancer without overt side effects.

Yin Y, Ni J, Chen M, Guo Y, Yeh S.
Department of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.
Shuyuan Yeh, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. Phone: 585-273-2750; Fax: 585-756-4133; E-mail: shuyuan_yeh@urmc.rochester.edu.



Abstract

PURPOSE: To determine the antitumor efficacy of using calcitriol combined with RRR-alpha-vitamin E succinate (VES) on prostate cancer. EXPERIMENTAL DESIGN: The effects of VES or VES in combination with calcitriol on the calcitriol target genes were evaluated by Western blot and real-time PCR. The antiproliferation effect of the combination in prostate cancer cells was evaluated by the combination index method. The role of the vitamin D(3) receptor (VDR) in the enhanced antitumor effects of the combination was confirmed by small interfering RNA knockdown strategy. Xenograft-bearing mice were used to reaffirm the antitumor efficacy of this combination. Pathohistology analyses and expressions of VDR and its target genes were analyzed in untreated and treated tumors. RESULTS: VES selectively increased VDR protein in different prostate cancer cells. Low doses of calcitriol combined with VES were significantly superior to the additive effect of individual treatments against prostate cancer cell proliferation. The expression of VDR target genes involved in antiproliferation were further sensitized in the presence of VES. Knockdown of VDR expression abolished the combination benefits in LNCaP and PC3 cells. Consistently, in prostate cancer xenograft models, VES enhanced the therapeutic efficacy of a tolerated dose of calcitriol yet without overt evidence of systemic toxicity and hypercalcemia. This notable in vivo effect was also accompanied by up-regulation of VDR target genes. CONCLUSIONS: Low-dose calcitriol combined with vitamin E analogue could be a solution to the calcemic side effect. The demonstration of superior antitumor activity of low-dose calcitriol plus VES provides the preclinical basis for developing a useful therapeutic strategy for prostate cancer.

PMID: 19118046 [PubMed - indexed for MEDLINE]Free Article

Translational Relevance

Because vitamin E succinate and calcitriol have been applied in different clinical trials in combination with other agents for prostate cancer therapy, it is a relatively small and close step to initiate clinical trials of vitamin E succinate plus calcitriol to treat prostate cancer. What is important is showing persuasive evidence to prove that combined vitamin E succinate and calcitriol to treat prostate cancer is effective. Our data indeed provide solid and supportive evidence both in prostate cancer cells and in preclinical animal cancer models. Thus, the potential impact of this study could be profound for developing an alternative and improved strategy to treat prostate cancer.

calcitriol(Vitamin D)not only synergistic w AI, but anti-prostaglandin,bone-conserving

Endocrinology. 2009 Nov 11. [Epub ahead of print]
Tissue-Selective Regulation of Aromatase Expression by Calcitriol: Implications for Breast Cancer Therapy.
Krishnan AV, Swami S, Peng L, Wang J, Moreno J, Feldman D.

Departments of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305.

Aromatase, the enzyme that catalyzes estrogen synthesis, is critical for the progression of estrogen receptor-positive breast cancer (BCa) in postmenopausal women. We show that calcitriol, the hormonally active form of vitamin D, regulates the expression of aromatase in a tissue-selective manner. Calcitriol significantly decreased aromatase expression in human BCa cells and adipocytes and caused substantial increases in human osteosarcoma cells (a bone cell model exhibiting osteoblast phenotype in culture) and modest increases in ovarian cancer cells. Calcitriol administration to immunocompromised mice bearing human BCa xenografts decreased aromatase mRNA levels in the tumors and the surrounding mammary adipose tissue but did not alter ovarian aromatase expression. In BCa cells, calcitriol also reduced the levels of prostaglandins (PGs), major stimulators of aromatase transcription, by suppressing the expression of cyclooxygenase-2 (which catalyzes PG synthesis) and increasing that of 15-hydroxyprostaglandin dehydrogenase (which catalyzes PG degradation). The mechanism of aromatase down-regulation by calcitriol in BCa cells is therefore 2-fold: a direct repression of aromatase transcription via promoter II through the vitamin D-response elements identified in this promoter and an indirect suppression by reducing the levels of PGs. Combinations of calcitriol with three different aromatase inhibitors (AIs) caused enhanced inhibition of BCa cell growth. The combination of calcitriol and an AI may have potential benefits for BCa therapy. In addition to augmenting the ability of AIs to inhibit BCa growth, calcitriol acting as a selective aromatase modulator that increases aromatase expression in bone would reduce the estrogen deprivation in bone caused by the AIs, thus ameliorating the AI-induced side effect of osteoporosis.

PMID: 19906814


Nutr Rev. 2007 Aug;65(8 Pt 2):S121-3.
Potentiation of the growth-inhibitory effects of vitamin D in prostate cancer by genistein.

Krishnan AV, Swami S, Moreno J, Bhattacharyya RB, Peehl DM, Feldman D.
Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building, S-025, Stanford, CA 94305, USA. krishnan@cmgm.stanford.edu
PMID: 17867387 [PubMed - indexed for MEDLINE]
LINK



Potentiation of the Growth Inhibitory Effects of Vitamin D in Prostate Cancer
By Genistein
Aruna V. Krishnan1, Srilatha Swami1, Jacqueline Moreno1, Rumi B. Bhattacharyya1, Donna M. Peehl2, and David Feldman1
1Department of Medicine, Division of Endocrinology, Stanford University School of Medicine2Department of Urology, Stanford University School of Medicine

Calcitriol, the hormonally active form of vitamin D, inhibits the growth and progression of several cancers. Inflammation has been postulated to play a role in the carcinogenic process of many cancers, including prostate cancer (PCa). Our recent research indicates that calcitriol exhibits anti-inflammatory actions that may contribute to its anti-cancer effects in PCa. Calcitriol inhibits the synthesis and actions of pro-inflammatory prostaglandins (PG) by three mechanisms:
(i) inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors, the mediators of PG actions. Our research also shows that genistein, an active component in soy is a potent inhibitor of vitamin D-24-hydroxylase, the enzyme that initiates the catabolism of calcitriol,
thereby increasing its biologically activity.
In addition, genistein also exerts independent regulatory effects on the PG pathway in PCa cells. Like calcitriol, genistein inhibits COX-2 expression in PCa cells leading to decreased synthesis of PGE2. Genistein also decreases EP and FP PG receptor expression thereby reducing the biological effects of PGE2. The combination of calcitriol and genistein acts in a cooperative way to inhibit the PG pathway as well as retard PCa cell growth. Both calcitriol and genistein are relatively safe with little toxicity associated with their intake. We therefore postulate that the combination of calcitriol and genistein is an attractive therapeutic option for the treatment and/or prevention of PCa.

J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):519-26.
Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

Trump DL, Hershberger PA, Bernardi RJ, Ahmed S, Muindi J, Fakih M, Yu WD, Johnson CS.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. donald.trump@roswellpark.org
1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

PMID: 15225831 [PubMed - indexed for MEDLINE]

Researcher in the study above says "No evidence for disease specificity ..effects are seen across all tumor histotypes"
Roswell Park is a comprehensive Cancer Center http://www.roswellpark.org/


Vitamin D3 better than metformin for insulin sensitivity

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http://www.tulsaworld.com/Scene/arti...4_DearPh185644

"a 2004 study published in the American Journal of Clinical Nutrition which found that raising a person's blood levels of vitamin D (from 25 to 75 nmol/l) could improve insulin sensitivity by a whopping 60 percent. "

"Compare that to metformin, one of our pharmaceutical gold-standards, which can dispose of blood sugar by a meager 13 percent "

"I suggest you ask your doctor if he minds you supplementing with about 5,000 IU "cholecalciferol" or vitamin D3 every morning."



Int J Endocrinol. 2010;2010:351385.
Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis.

Alvarez JA, Ashraf A.
Department of Nutrition Sciences, University of Alabama at Birmingham, AL 35233, USA.
Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associations with insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitamin D supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies. Future studies, including cross-sectional and prospective, should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed, placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucose homeostasis.

PMID: 20011094 [PubMed - in process]




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Vitamin D Good for Breast Cancer Patients

FRIDAY, Oct. 9 (HealthDay News) -- Many breast cancer patients have low levels of vitamin D, which could lead to weaker bones and increased risk of fractures, say U.S. researchers who recommend high doses of vitamin D for them.
"Vitamin D is essential to maintaining bone health, and women with breast cancer have accelerated bone loss due to the nature of hormone therapy and chemotherapy. It's important for women and their doctors to work together to boost their vitamin D intake," Luke Peppone, a research assistant professor of radiation oncology at the University of Rochester Medical Center, said in a news release from the medical cwnter.
Peppone and colleagues studied 166 women undergoing treatment for breast cancer and found that nearly 70 percent had low levels of vitamin D in their blood. The average level among the women was 27 nanograms of vitamin D per milliliter of blood. Levels of 32 nanograms per milliliter are adequate, according to the U.S. Institute of Medicine.
The lowest levels of vitamin D were in non-whites and those with late-stage breast cancer.
The researchers found that weekly supplementation with high doses of vitamin D (50,000 IU or more) boosted the levels of the vitamin among all the women.
The study was to be presented Oct. 8 at the American Society of Clinical Oncology's breast cancer symposium in San Francisco.
Previous studies have shown that nearly half of all women and men have vitamin D levels below 32 nanograms per milliliter. Along with strengthening bones, vitamin D plays an important role in cell growth and keeping the immune system strong. People obtain Vitamin D through exposure to sunlight and from foods such as milk and fortified cereals.


Video: Dr. Feldman at Stanford: Vitamin D: Not just for bones
http://med.stanford.edu/medcast/2008/vitamind.html

	David Feldman, MD, professor of medicine, explores the biological action of Vitamin D beyond its widely understood role in the formation and maintenance of bone. Emerging therapeutic uses of the vitamin cover a range of conditions, including breast and prostate cancer, chronic kidney disease and arthritis.

Immunol Invest. 2009;38(5):365-82.
Dietary vitamin D3 restriction influences tumor growth, but not the ability to generate an antigen-specific immune response in OTII transgenic mice.

Goldstein BD, Kurt RA.
Department of Biology, Lafayette College, Easton, Pennsylvania 18042, USA.
Initially, we wanted to know whether dietary vitamin D(3) restriction would influence growth and metastasis of the 4T1 murine mammary carcinoma. We confirmed serum 25(OH)D levels were modulated by dietary vitamin D(3) restriction, mice were healthy, and when challenged with the 4T1 tumor alterations in tumor growth, but not metastasis were evident. Tumors grew more rapidly in mice on the vitamin D(3) restricted diet. To delineate whether dietary vitamin D(3) restriction influenced the ability to generate an antigen-specific immune response we used OTII transgenic mice which express a T cell receptor specific for ovalbumin. We found that dietary vitamin D(3) restriction did not influence the health of OTII mice, the number of circulating CD3/CD4(+), CD3/CD8(+), CD4/CD25(+) T cells, nor the ability to generate CD11c(+) bone-marrow derived dendritic cells. T cells from OTII mice maintained on the vitamin D(3) restricted diet also exhibited no significant alterations in proliferative capacity or ability to secrete IFN-gamma or IL-4 in an antigen-specific manner. Yet, EL-4 tumors grew more rapidly in OTII mice on the vitamin D(3) restricted diet. These data show that dietary vitamin D(3) restriction impacts tumor growth, but not the ability to generate an antigen-specific immune response.

PMID: 19811414 [PubMed - in process]




J Steroid Biochem Mol Biol. 2003 Feb;84(2-3):149-57.
Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells.

Wietzke JA, Welsh J.
Department of Biological Sciences, University of Notre Dame, IN 46556, USA.
1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a steroid hormone derived from Vitamin D(3), is a negative growth regulator of breast cancer cells, and Vitamin D(3) analogs represent a novel treatment approach for human cancer. Elucidation of Vitamin D(3) receptor (VDR) regulation may reveal strategies to sensitize cancer cells to the effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. We have previously characterized an estrogen responsive promoter region (800 bp upstream of exon 1c) in the human VDR gene, and the present studies examined regulation of this VDR promoter region by two phytoestrogens, resveratrol (present in red wine) and genistein (present in soy). We transiently transfected a VDR promoter luciferase construct into the estrogen receptor (ER) positive human breast cancer cell lines T47D and MCF-7, and treated with 0.4-4 microM resveratrol or 5-500 nM genistein. Both phytoestrogens up-regulated the transcription of the VDR promoter, as measured by reporter gene activity, approximately two-fold compared to vehicle treated cells. Co-treatment with the anti-estrogen tamoxifen (TAM) in T47D cells and transfection in an estrogen receptor negative breast cancer cell line demonstrated that the effects of phytoestrogens on the VDR promoter are dependent on estrogen receptor. Resveratrol and genistein also increased VDR protein expression as detected by Western blotting. Treatment with resveratrol had no effect on cell number or cell cycle profile, while treatment with genistein increased cell number. Because resveratrol could up-regulate VDR without increasing breast cancer cell growth, we hypothesized that resveratrol mediated increase in VDR expression would sensitize breast cancer cells to the effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. In support of this hypothesis, both T47D and MCF-7 cells pre-treated with resveratrol exhibited increased VDR mediated transactivation of a Vitamin D(3) responsive promoter compared to cells pre-treated with vehicle. In addition, co-treatment with resveratrol enhanced the growth inhibitory effects of 1,25-dihydroxyvitamin D(3) and the Vitamin D(3) analog EB1089. These data support the concept that dietary factors, such as phytoestrogens, may impact on breast cancer cell sensitivity to Vitamin D(3) analogs through regulation of the VDR promoter.

PMID: 12710998 [PubMed - indexed for MEDLINE]



Cancer Nurs. 2009 Mar-Apr;32(2):143-50.
Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy.

Waltman NL, Ott CD, Twiss JJ, Gross GJ, Lindsey AM.
College of Nursing, University of Nebraska Medical Center, Lincoln, NE, USA.
Breast cancer survivors (BCSs) on aromatase inhibitor (AI) therapy often experience musculoskeletal symptoms (joint pain and stiffness, bone and muscle pain, and muscle weakness), and these musculoskeletal symptoms may be related to low serum levels of vitamin D. The primary purpose of this pilot exploratory study was to determine whether serum levels of 25-hydroxyvitamin D (25[OH]D) concentration were below normal (<30 ng/mL) in 29 BCSs on AI therapy and if musculoskeletal symptoms were related to these low vitamin D levels. The mean (SD) serum 25(OH)D level was 25.62 (4.93) ng/mL; 86% (n = 25) had levels below 30 ng/mL. Patients reported muscle pain in the neck and back, and there was a significant inverse correlation between pain intensity and serum 25(OH)D levels (r = -0.422; P < .05 [2 tailed]). This sample of BCSs taking AIs had below normal levels of serum 25(OH)D despite vitamin D supplements. This is one of the few studies to document a significant relationship between vitamin D levels and muscle pain in BCSs on AI therapy. Findings from this pilot study can be used to inform future studies examining musculoskeletal symptoms in BCSs on AI therapy and relationships with low serum levels of vitamin D.

PMID: 19125120 [PubMed - indexed for MEDLINE]



Cancer Cell. 2010 Mar 16;17(3):273-285.
Modulation of the Vitamin D3 Response by Cancer-Associated Mutant p53.

Stambolsky P, Tabach Y, Fontemaggi G, Weisz L, Maor-Aloni R, Sigfried Z, Shiff I, Kogan I, Shay M, Kalo E, Blandino G, Simon I, Oren M, Rotter V.
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
The p53 gene is mutated in many human tumors. Cells of such tumors often contain abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the vitamin D receptor (VDR) response element as overrepresented in promoter sequences bound by mutp53. We report that mutp53 can interact functionally and physically with VDR. Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting the transactivation of some genes and relieving the repression of others. Furthermore, mutp53 increases the nuclear accumulation of VDR. Importantly, mutp53 converts vitamin D into an antiapoptotic agent. Thus, p53 status can determine the biological impact of vitamin D on tumor cells. Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 20227041 [PubMed - as supplied by publisher]